EP0969883A1

EP0969883A1 - Implant for subcutaneous or intradermal injection

Info

Publication number: EP0969883A1
Application number: EP98932196A
Authority: EP
Inventors: Jérôme ASIUS; Hatem Fessi; Franck Gouchet; Bénédicte Laglenne; Elisabeth Laugier-Laglenne
Original assignee: Biopharmex Holdings SA
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1997-06-13
Filing date: 1998-06-12
Publication date: 2000-01-12
Anticipated expiration: 2018-06-12
Also published as: US8414657B2; BR9804962A; US7731758B2; DK0969883T3; DE69819694T2; FR2764514B1; ES2210776T3; IL128210A; KR100543560B1; RU2214283C2; IL128210A0; PT969883E; DE69819694D1; US20100221684A1; US6716251B1; RO118261B1; HUP0001465A2; HK1025268A1; HU228462B1; FR2764514A1

Abstract

The invention concerns an injection implant for filling up wrinkles, thin lines, skin cracks and scars, for reparative or plastic surgery, aesthetic dermatology, and for filling up gums in dental treatment. The invention concerns the use of biologically absorbable polymer microspheres or microparticles suspended in a gel. Said suspension is produced either ready-for-use or freeze-dried. The biological absorbability of the microspheres is controlled and enables the production of implants having well defined persistence and deliberately limited to 3 years.

Description

IMPLANT INJECTABLE BY SUBCUTANEOUS OR INTRADERMAL ROUTE

The present invention relates to an injectable implant subcutaneously or intradermally, intended for use in humans in restorative or plastic surgery and in cosmetic dermatology, for the filling of wrinkles, fine lines, skin depressions, acne scars and hairs scars, as well as in dentistry for filling the gums.

To date, a number of products have been used for this purpose. Each product has advantages and disadvantages.

The silicone gel (or silicone oil) is easy to use. However, it has been observed, after injection, the migration of silicone droplets into the tissues situated below the injection point, by simple gravity. Silicone is frequently the cause of chronic inflammation, the formation of granulomas, and even late allergic reactions. Silicone is not biodegradable, and it is often found in the liver.

Teflon paste is a suspension of polytetrafluoroethylene particles (diameter 10 to 100 μ) in glycerin. This product, in many cases, caused severe and chronic serous infections, and had to be removed after a few months from the dermal and subdermal tissues for most patients. It has also been proven that small particles of polytetrafluoroethylene have been found in the liver.

Collagen suspensions have been widely used in the past ten years. The results were however rather disappointing insofar as the collagen is absorbed in 1 to 3 months. Allergic reactions are also seen in about 2% of patients. Finally, it should be noted that the collagen is of bovine origin. Biological samples from the patient himself: the idea was certainly interesting, but clinical experience has shown the failure to reprimpiate the fat cells, which are absorbed and disappear within a few weeks.

Another system consisted in adding the patient's plasma to a bovine and porcine collagen gelatin. The results are even more disappointing, and the product is of animal origin.

Hyaluronate gels presented a good alternative due to their bio-compatibility and their absence of toxicity. They are also widely used in eye surgery. However, their rapid bio-absorbability (maximum 2 months) makes them ineffective for use in plastic surgery.

Bioplastics are polymerized silicone particles (diameter 70 to 140 μm) dispersed in polyvinylpyrrolidone. The product had to be removed due to the chronic inflammation and the rejection reactions it caused.

Polymethylmethacrylate (PMMA) microspheres with a diameter of 20 to 40 μm in suspension either in a gelatin solution or in a collagen solution. PMMA is not biodegradable, but there is a lack of experience to know what this implant gives after 5 or 6 years. Furthermore, the vector remains a solution of collagen of bovine origin, with the allergy problems that it is known to have.

The object of the invention is to remedy the drawbacks of known products.

The invention makes use of microspheres or microparticles consisting of a neutral polymer chosen for its harmlessness and already used widely by the pharmaceutical industry, whether orally or parenterally. The implant according to the invention combines the convenience of use without prior manipulation, the product's syringability, the resorbability in a controlled time of the polymer like carrier gel, the absence of allergenicity of the product, which makes any prior test unnecessary. .

The microspheres or microparticles must have a controlled bio-absorbability ensuring a resorbability time of between 1 and 3 years. This means that the polymer will degrade after injection in situ into low molecular weight compounds which will be eliminated from the body by natural processes. In no case does a non-absorbable implant appear desirable. It is always a foreign body placed in a living tissue.

The microspheres or microparticles are suspended in a gel. They must have a diameter greater than 5 μm, and preferably greater than 20 μm, so as not to be absorbed by the macrophages. They must have a diameter of less than 150 μm, and preferably less than 40 μm, so that on the one hand they can be injected with a fine needle and on the other hand they do not create granular clumps under the finger.

Two families of polymers essentially meet the above definition: polycaprolactones (and in particular poly-e-caprolactones), as well as polylactides (polylactic acids or PLA), polyglycolides (polyglycolic acids or PGA) and their copolymers (polylac acids - ticks-co-glycolics or PLAGA).

Taking into account the numerous studies already carried out and the good knowledge of the products, in particular as regards the manufacture of microspheres and resorbability, it seems advantageous to use a mixture of polylactic acid (PLA) and polylactic acid-co- glycolic (PLAGA). The proportions of each of these two acids make it possible to determine the persistence of the product. Numerous tests have also led to favoring a polymer constituted by a poly-L-lactic acid (crystalline), a poly-D-lactic acid (amorphous), or a mixture of these two acids. Its molecular mass calculated by viscosimetry is advantageously between 70,000 and 175,000 Dalton, and preferably between 120,000 and 170,000 Dalton, an intrinsic viscosity between 3 and 4 dl / g, and preferably between 3.35 and 3.65 dl / g , a specific rotation between -150 and -160 °, a melting point between 178.0 and 190, 1 ° C, a heat of fusion between 85.0 J / g and 90.0 J / g, a amount of residual solvents <0.01% and a proportion of residual monomer (lactic acid) <0.1%. Such a product is available from PURAC 3I0CHEM in Gorinchem (Netherlands).

Bio-absorbable synthetic polymers have been studied for fifteen years under the direction of Michel VERT, director of research at C.N.R.S. The first clinical uses of PLA began in 1981 for various indications in facial trauma. Lactic acid polymers have seen their use systematized in the context of bio-absorbable surgical implants. PLA's medical applications are today diversified and extensive (bone surgery, maxillofacial surgery, pharmacological formulations with controlled release: implants, microspheres, nanospheres, vaccines).

The degradation of lactic acid and / or glycolic acid polymers in a biological medium takes place exclusively by a non-specific chemical hydrolysis mechanism. The products of this hydrolysis are then metabolized and eliminated by the human body. The chemical hydrolysis of the polymer is complete; it intervenes all the more quickly when its amorphous character is pronounced and when its molecular mass is low. Thus, the resorbability time can be adjusted by acting on the composition of the mixture and / or on the molecular mass of the polymer (s). The biocompatibility of PLA and PLAGA polymers makes them excellent supports for cell growth and tissue regeneration. The microspheres or micrcarticles are included in a gel. This gel, used as a vector to maintain the microspheres or microparticles in homogeneous suspension, is absorbable in about 2 months, which corresponds to the time necessary for the creation of fibrosis around the microspheres or microparticles. It mainly consists of water for injections and a gelling agent authorized for injection: cellulose derivatives, and more particularly carboxymethylcellulose (CMC) at a mass concentration of 0.1 to 7.5%, and preferably from 0.1 to 5.0%. Hydroxypropylmethylcellulose (HPMC) can also be used, which is commonly used in intraocular injection for cataract operations. A synthetic hyaiuronic acid can also be used, used for intraocular injections and subcutaneous injections. It is also possible to use lactic acid esters, caproic acid esters, etc.

The good dispersion of the microspheres or microparticles and the homogeneity of the gel will be ensured by the use of a surfactant, chosen for its safety and its authorized use in subcutaneous and intra-dermal. Polyoxyethylene sorbitan monooleate (sold under the name Tween 80) or pluronic acid will be used.

The product can be presented in sterile pre-filled syringes ready for use, provided with a needle, or in bottles of sterile suspension. It can also be presented in a vial containing a lyophilisate accompanied by an ampoule of sterile water (water for injection), or in a pre-filled syringe with two compartments, one containing the lyophilisate of microspheres or microparticles, the other containing water for injection.

The implant does not require an allergenicity test. It does not contain any animal products. The implant manufacturing protocol is described below, in the case of a ready-to-use suspension of microspheres.

A. Preparation of microspheres of lactic acid polymer. The conventional technique is used by solvent evaporation, or the technique known as controlled precipitation, or any other technique allowing microspheres of desired size to be obtained.

B. Preparation of a gel of sufficient viscosity to maintain the microspheres in suspension. This viscosity will be adapted as a function of the particle size of the microspheres and the proportion of microspheres dispersed in the gel. This proportion will be from 50 to 300 g / l, and preferably from 60 to 200 g / l.

C. Distribution of the gel in syringes or in vials, in a controlled atmosphere (class 10 ⁴ ).

D. Sterilization of vials or syringes, or use of a process which makes the finished product suitable for subcutaneous injection.

The manufacturing protocol is described below in the case of lyophilized PLA microparticles, whether it is polymer L, polymer D or a mixture of these.

A. Cryogenic grinding of the PLA under gaseous nitrogen filtered at 0.22 μm, at a temperature below -80 ° C., on a 100 μm screening grid.

B. Screening of the microparticles on a 100 μm stainless steel screen.

C. Preparation of the lyophilization medium including the dissolution, with stirring, of CMC (gelling agent), of pyrogenic mannitol (cryoprotective agent), and of polysorbate (surfactant) in water for injection preparation. ble, filtration at 0.22 μm of the solution obtained under gaseous nitrogen filtered at 0.22 μm, and sterilization in an autoclave for 20 minutes at 121.5 ° C.

D. Distribution of microparticles at a rate of 100 mg per vial with a nominal capacity of 4 ml.

E. Distribution of the lyophilization medium at a rate of 1.05 ± 0.05 g in the vials already containing the microparticles of polylactic acid.

F. Dispersion of the microparticles in the lyophilization medium by an ultrasonic dispersion system, in order to obtain a homogeneous suspension.

G. Pre-capping of vials using pillar caps (specific for freeze-drying), rapid freezing below -70 ° C, storage of frozen vials below -40 ° C, and finally freeze-drying and automatic capping of vials .

H. Capping and candling of the bottles, before sterilization by irradiation y.

Of course, it is possible to combine the procedures described above, for example to obtain a suspension of microparticles ready for use, or a lyophilisate of microspheres, the microparticles or microspheres being made up of any one of the polymers mentioned above and their mixtures.

EXAMPLE 1

2 g of PLA are dissolved in 20 ml of an organic solvent (ethyl acetate). This solution is dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring with a vortex is maintained until the solvent has evaporated and microspheres with an average diameter of 40 μm are formed. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0.5% by mass). After moderate agitation, the distribution is carried out.

EXAMPLE 2

2 g of PLA are dissolved in 20 ml of an organic solvent (methylene chloride). This solution is dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring with a vortex is maintained until the solvent has evaporated and microspheres with an average diameter of 80 μm are formed. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0.5% by mass). After moderate agitation, the distribution is carried out.

EXAMPLE 3

2 g of PLA are dissolved in 20 ml of an organic solvent

(chloroform). This solution is dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring with a vortex is maintained until the solvent has evaporated and microspheres with an average diameter of 50 μm are formed. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and HPMC (1% by mass). After moderate agitation, the distribution is carried out.

EXAMPLE 4

600 g of polylactic acid are freeze-grinded, with a final particle size of between 20 and 100 μm, with a median of 40 μm. These microparticles are distributed at a rate of 100 mg per bottle.

6.5 kg of lyophilization medium are produced by dissolving 97.5 g of sodium CMC, 276.25 g of pyrogen-free mannitol, and 6.5 g of polysorbate 80 in qs 6.5 liters of water for injection. This medium is distributed at a rate of 1 g per bottle. Animal tests (hairless mice and New Zealand rabbits) were carried out with the products of examples 1 to 4. The results are identical, and are observed during the first two months, and from the eighth day after the injection. , the appearance of giant cells surrounding the polylactic acid crystals in a network, then their transformation by creation of a fibrosis which reconstitutes the subcutaneous tissue.

Claims

claims

1. Injectable implant for human administration consisting of microspheres or bio-absorbable microparticles suspended in a gel.

2. Implant according to claim 1, characterized in that the microspheres or microparticles consist of at least one polymer chosen from poly-e-caprolactone, polymers of lactic acid, polymers of glycolic acid and polymers d co-glycolic lactic acid.

3. Implant according to one of claims 1 and 2, characterized in that the proportion of microspheres or microparticles in the gel is from 50 to 300 g / 1, and preferably from 60 to 200 g / 1.

4. Implant according to one of the preceding claims, characterized in that the microspheres or microparticles have an average diameter of 5 to 150 μm, and preferably from 20 to 80 μm.

5. Implant according to one of the preceding claims, characterized in that the microspheres or microparticles are bio-absorbable in a period of 1 year to 3 years.

6. Implant according to one of the preceding claims, characterized in that said polymer is a polylactic acid chosen from poly-L-lactic acid, poly-D-lactic acid and mixtures thereof.

7. Implant according to claim 6, characterized in that the polylactic acid has a molecular mass between 70,000 and 175,000 Dalton, and preferably between 120,000 and 170,000 Dalton, an intrinsic viscosity between 3 and 4 dl / g, and preferably between 3.35 and 3.65 dl / g, a percentage of residual monomer <0.1% and a percentage of residual solvents <0.01%.

8. Implant according to one of the preceding claims, characterized in that the gel mainly includes as a gelling agent carboxymethylcellulose (CMC) or hydroxypropylmethylcellulose (HPMC) at a weight concentration of 0.1 to 7.5%, and preferably from 0.1 to 5.0%.

9. Lyophilisate obtained by lyophilization of a product according to one of the preceding claims, and suitable for reconstituting an injectable implant by adding water for injectable preparation.